Despite the longstanding, massive, effort to develop effective treatments for diabetes, metabolic syndrome, obesity, and related metabolic conditions, the number of people worldwide who suffer from them is rapidly growing. These conditions result in numerous medical complications, a lowered quality of life, shortened lifespan, lost work productivity, a strain on medical systems, and a burden on medical insurance providers that translates into increased costs for all.
Type II diabetes treatments in use or development are designed to lower blood glucose levels. They include mimetics of GLP-1 (glucagon-like peptide-1), a hormone that plays a key role in regulating insulin, glucose and hunger. Examples of mimetics are the GLP-1 receptor agonist, Exenatide (Byetta) and the GLP-1 analog Liraglutide. Other drugs inhibit DPP-IV, an enzyme that rapidly degrades endogenous GLP-1. Exenatide is a GLP-1 receptor agonist that is degraded more slowly by DPP-IV. Liraglutide, a GLP-1 analog, is attached to a fatty acid molecule that binds to albumin and slows the rate of GLP-1 release and its degradation. (See, e.g., Nicolucci, et al., 2008, “Incretin-based therapies: a new potential treatment approach to overcome clinical inertia in type 2 diabetes,” Acta Biomedica 79(3):184-91 and U.S. Pat. No. 5,424,286 “Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same.”)
Current obesity treatments include two FDA-approved drugs. Orlistat (Xenical) reduces intestinal fat absorption by inhibiting pancreatic lipase. Sibutramine (Meridia), decreases appetite by inhibiting deactivation of the neurotransmitters norepinephrine, serotonin, and dopamine. Undesirable side-effects, including effects on cholesterol levels, have been reported with these drugs. (See, e.g., NIH Publication No. 07-4191 “Prescription Medications for the Treatment of Obesity” U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Dec. 2007: 1-8) Surgical treatments including gastric bypass surgery and gastric banding are available, but only in extreme cases. These procedures can be dangerous, and furthermore are not appropriate options for patients with more modest weight loss goals.
Certain intestinal cells, L cells, have been reported to produce GLP-1 in response to glucose and amino acid stimulation. These and other such “enteroendocrine cells” also produce other hormones involved in processes relating to glucose metabolism, including oxyntomodulin, reported to ameliorate glucose intolerance and suppress appetite, PYY (peptide YY), also observed to suppress appetite, CCK (cholecystokinin), which stimulates the digestion of fat and protein and also reduces food intake, GLP-2, which induces gut cell proliferation, and GIP (gastric inhibitory polypeptide, also called glucose-dependent insulinotropic peptide), an incretin secreted from the intestinal K cells that augments glucose-dependent insulin secretion. (See, e.g., Jang, et al., 2007, “Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1,” PNAS 104(38):15069-74 and Parlevliet, et al., 2007, “Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet,” Am J Physiol Endocrinol Metab 294(1):E142-7.)
It has also been reported that there are taste receptors present on the L-cells and K-cells in the intestine (Hofer, et al., 1996, “Taste receptor-like cells in the rat gut identified by expression of alpha-gustducin” Proc Natl Acad Sci USA 93:6631-6634). The sweet taste receptors are heterodimers of the T1R2 and T1R3GPCRs and are identical to those found on taste buds. The umami receptors are T1R1 and T1R3 heterodimers (Xu, et al., 2004, “Different functional roles of T1R subunits in the heteromeric taste receptors,” Proc Natl Acad Sci USA 101: 14258-14263 and Sternini, et al., 2008, “Enteroendocrine cells: a site of ‘taste’ in gastrointestinal chemosensing,” Curr Opin Endocrinol Diabetes Obes 15: 73-78). Stimulation of these receptors by luminal nutrients results in apical secretion of L-cell products such as GLP-1, PYY, oxyntomodulin and glycentin, and K-cell products such as GIP, and into the portal vein (Jang, et al., 2007, PNAS 104(38):15069-74). In a glucose-dependent manner, GLP-1 and GIP increase insulin release from beta cells (an effect known as the incretin effect). In addition, GLP-1 inhibits glucagon release and gastric emptying. GLP-1, oxyntomodulin and PYY 3-36 are considered to be satiety signals (Strader, et al., 2005, “Gastrointestinal hormones and food intake,” Gastroenterology 128: 175-191). Receptors for fatty acids (e.g., GPR40 and/or GPR120) (Hirasawa, et al., 2005, Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120, Nat Med 11: 90-94) and bile acids (e.g., Gpbar1/M-Bar/TGR5) (Maruyama, et al., 2006, “Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice.” J Endocrinol 191: 197-205 and Kawamata, et al., 2003, “A G protein-coupled receptor responsive to bile acids,” J Biol Chem 278: 9435-9440) are also present in enteroendocrine cell lines. There are also a large number of T2Rs, which comprise the bitter receptors. The sour and salty receptors, which likely include ion channels, have not been completely characterized. Activation of taste receptors, for example, activation of the sweet receptor by glucose stimulation, has been reported to result in the release of GLP-1 and other enteroendocrine cell products.
Although many nonmetabolized “tastants” recognized by taste receptors have been identified, there are currently none that have been approved for use in increasing production (biosynthesis) of GLP-1 or related hormones. Furthermore, a number of reports suggest that oral delivery of sweet tastants are not associated with GLP-1 release. (See, e.g., Ma, et al., 2009, “Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects,” American Journal Physiol. Gastrointest. Liver Physiol., 2009, 296(4):G735-9, Epub 2009 Feb. 12 and Fujita, et al., 2009, “Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo,” American Journal Physiol. Endocrinol. Metab. 296(3):E473-9. Epub 2008 Dec. 23.) Nonetheless, it would be of great value in the treatment of diabetes, metabolic syndrome, obesity, and related disorders to determine how to use chemosensory receptor ligands to treat disorders associated with chemosensory receptors by modulating enteroendocrine cell hormones.